Shih J H, Liu W F, Lee S F, Lee J D, Ma C, Lin C H
Chemical Systems Division, CSIST, Lung-Tan, Taiwan, R.O.C.
Pharmacol Biochem Behav. 1991 Mar;38(3):549-53. doi: 10.1016/0091-3057(91)90012-q.
Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3-40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (less than or equal to 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (greater than 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED50 was calculated as 23.3 (17.9-28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (less than or equal to 12 mg/kg) had an onset latency within 40-80 min and a duration of 20-80 min, whereas high doses (greater than or equal to 24 mg/kg) had an onset latency of 20-40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30-120.mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.
溴吡斯的明（Pyr）是目前治疗重症肌无力的首选药物，已被建议用于治疗阿尔茨海默病性痴呆，并作为有机磷酸酯胆碱酯酶抑制剂中毒的预防性治疗药物。本研究旨在评估在宽泛剂量范围（3 - 40mg/kg）内急性口服Pyr对维持在多重固定比率（FR - 20）超时强化饮水奖励时间表下的大鼠杠杆按压行为的剂量反应和时程效应。该药物在FR反应的总体速率上产生了剂量依赖性的双相反应抑制。低剂量的Pyr（小于或等于12mg/kg）未引起明显的毒性迹象，仅适度降低反应速率，主要是由于反应率下降。而高剂量的Pyr（大于24mg/kg）产生外周胆碱能中毒的明显迹象，显著抑制总体反应，主要是由于反应停止。行为破坏的最低有效剂量为6mg/kg，ED50计算为23.3（17.9 - 28.7）mg/kg。行为破坏的时程数据表明，低剂量的Pyr（小于或等于12mg/kg）起效潜伏期在40 - 80分钟内，持续时间为20 - 80分钟，而高剂量（大于或等于24mg/kg）起效潜伏期为20 - 40分钟，持续时间大于80分钟。这些结果表明，推荐的人类治疗或预防方案，即每8小时口服30 - 120mg Pyr，可能会对行为表现产生不利影响。
